Insufficient ferroptosis in radiation-induced tumor cells promote Treg cell generation to induce radiotherapy resistance.

Recently, cellular mechanisms underlying radioresistance in the tumor microenvironment (TME) attract increasing attention, but how the resistant tumor cells reshape the TME is still unclear. In this study, we find that the ferroptosis-resistant genes are upregulated in radioresistant tumor cells, resulting in the impairment of radiation-induced ferroptosis in radioresistant cells.

Additionally, the release of transforming growth factor beta 1 (TGF-β1) is increased in radioresistant tumor cells, contributing to Treg cell infiltration in radioresistant tumor tissues. Hence, the ferroptosis inducer sorafenib enhances the sensitivity of local irradiation in radioresistant tumor models by inhibiting Treg cell infiltration.

Furthermore, database analysis of The Cancer Genome Atlas shows that the score of ferroptosis-resistant genes positively correlates with both TGF-β1 expression level and Treg cell infiltration score in several types of tumor tissues. The ferroptosis-resistance score of TME is higher in non-responders than in responders of colorectal cancer and breast cancer.

These findings suggest irradiation-induced insufficient ferroptosis promotes the accumulation of Treg cells via the release of TGF-β1, providing new insights for clinical trials designing the combination of ferroptosis-inducing chemotherapy with radiotherapy to overcome radioresistance.